DESCRIPTION The organization and mechanisms of the fast-acting neurotransmitters (GABA and glutamate) in the neocortex have been studied extensively. On the other hand, data about the modes and sites of action of the modulatory neurotransmitters in the neocortex are scant. The investigators lack knowledge about the effects of modulators on synaptic transmission. The goal of the proposed research is to examine the influence of selected modulatory transmitters on specific axonal pathways. The studies will test a general hypothesis: modulators differentially regulate specific synaptic tracts in the neocortex. Using intracellular recording techniques in thalamocortical slices from mouse brains, we will examine and characterize the effects of three different modulatory neurotransmitters (acetylcholine, norepinephrine, and the actions of GABA on GABA-B receptors) on synaptic transmission, between specific tracts and identified neuronal types: 1) thalamocortical and intracortical pathways onto single, layer 5 pyramidal cells will be selectively activated, and 2) isolated inhibitory inputs will be evoked onto single, layer 5 pyramidal cells. In addition, they will examine the influence of modulators on the frequency-sensitivity of each synaptic tract. The modulatory transmitter systems have been implicated in many functions and dysfunctions of the cerebral cortex, and are essential for normal brain development. This study will advance significantly an understanding of cortical organization and the mechanisms by which the modulatory transmitters affect activity in complex cortical circuits.